Methods and systems for treating cardiac malfunction

ABSTRACT

Methods and systems for treating cardiac malfunction are disclosed, which according to an embodiment, may involve delivering a stimulation pattern of stimulation pulses to at least one cardiac chamber of a heart, with at least one of the stimulation pulses having a first stimulation setting configured to reduce at least one of end systolic volume (ESV) and end diastolic volume (EDV) in the heart and at least one of the stimulation pulses having a second stimulation setting different from the first stimulation setting, and with the stimulation pattern being configured to reduce the at least one of end systolic volume (ESV) and end diastolic volume (EDV) by at least 5% and maintain the at least one of end systolic volume (ESV) and end diastolic volume (EDV) on average at such reduced volume for a time period of at least one hour.

This application is a continuation of U.S. application Ser. No.15/259,282, filed Sep. 8, 2016, now U.S. Pat. No. 10,342,982, issuedJul. 9, 2019, which claims the benefit of U.S. Provisional ApplicationNo. 62/217,299, filed Sep. 11, 2015, both of which are hereinincorporated by reference in their entirety.

BACKGROUND

The present embodiments relate to the field of treating cardiacmalfunction, and more particularly, to methods and systems forstimulating the heart to treat cardiac malfunction, such as congestiveheart failure.

SUMMARY

Methods and systems for treating cardiac malfunction are disclosed.

In one aspect, a method for treating cardiac malfunction may includedelivering a stimulation pattern of stimulation pulses to at least onecardiac chamber of a heart. At least one of the stimulation pulses mayhave a first stimulation setting configured to reduce at least one ofend systolic volume (ESV) and end diastolic volume (EDV) in the heart,and at least one of the stimulation pulses may have a second stimulationsetting different from the first stimulation setting. The stimulationpattern may be configured to reduce the at least one of end systolicvolume (ESV) and end diastolic volume (EDV) by at least 5% and tomaintain the at least one of end systolic volume (ESV) and end diastolicvolume (EDV) on average at such reduced volume for a time period of atleast one hour.

In another aspect, a system for treating cardiac malfunction may includea stimulation circuit and at least one controller. The stimulationcircuit may be configured to deliver a stimulation pulse to at least onecardiac chamber of a heart of a patient. The at least one controller maybe configured to execute delivery of a stimulation pattern ofstimulation pulses to the at least one cardiac chamber. At least one ofthe stimulation pulses may have a first stimulation setting configuredto reduce at least one of end systolic volume (ESV) and end diastolicvolume (EDV) in the heart, and at least one of the stimulation pulsesmay have a second stimulation setting different from the firststimulation setting. The stimulation pattern may be configured to reducethe at least one of end systolic volume (ESV) and end diastolic volume(EDV) by at least 5% and maintain the at least one of the end systolicvolume (ESV) and end diastolic volume (EDV) on average at such reducedvolume for a time period of at least one hour.

Other systems, methods, features, and advantages of the presentembodiments will be, or will become, apparent to one of ordinary skillin the art upon examination of the following figures and detaileddescription. It is intended that all such additional systems, methods,features and advantages be included within this description and thissummary, be within the scope of the embodiments, and be protected by thefollowing claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments can be better understood with reference to the followingdrawings and description. The components in the figures are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the embodiments. Moreover, in the figures, likereference numerals designate corresponding parts throughout thedifferent views.

FIG. 1 is a plot illustrating change in end systolic volume (ESV) frombaseline (BL) as a function of activation time, according to anembodiment;

FIG. 2 is a plot illustrating change in end diastolic volume (EDV) frombaseline (BL) as a function of activation time, according to anembodiment;

FIG. 3 is a plot illustrating change in ejection fraction (EF) frombaseline (BL) as a function of activation time, according to anembodiment;

FIG. 4 is a plot illustrating change in end systolic volume (ESV) frombaseline (BL) as a function of activation time over a longer period(about twenty-four months), according to a second embodiment;

FIG. 5 a plot illustrating change in end diastolic volume (EDV) frombaseline (BL) as a function of activation time over the longer period(about twenty-four months), according to the second embodiment;

FIG. 6 is a plot illustrating change in ejection fraction (EF) frombaseline (BL) as a function of activation time over the longer period(about twenty-four months), according to the second embodiment;

FIG. 7 is a flow chart illustrating an exemplary method for treatingcardiac malfunction, according to an embodiment; and

FIG. 8 is a schematic drawing illustrating an exemplary system fortreating cardiac malfunction, which may perform one or more of themethods described herein, such as the method of FIG. 7.

DETAILED DESCRIPTION

A healthy cardiac contraction cycle includes two phases: a systole and adiastole. The systole is a period of cardiac contraction, commencingwith ventricular contraction. The systole causes blood to be ejectedfrom the heart and into the vascular system. At the end of thiscontraction, cardiac muscles relax. This period of relaxation is thediastole. During diastole, the heart passively fills with blood from thevascular system and at the end of diastole the atria contract andprovide additional filling to the ventricle. Accordingly, at the end ofthe diastole and just before the heart begins to contract, cardiac bloodvolume peaks. This peak volume is the end diastolic volume (EDV). At theend of the systole, when contraction ends and cardiac filling is aboutto commence, cardiac blood volume reaches a minimal value. This minimalvolume is the end systolic volume (ESV). The amount of blood ejected ina heartbeat is known as the stroke volume (SV) and equals the differencebetween end diastolic volume (EDV) and end systolic volume (ESV). Theejection fraction (EF) is the fraction of blood that is ejected by theheart (i.e., SV divided by EDV).

Cardiac remodeling is a phenomenon that results from cardiac load orinjury, and is an accepted determinant of the clinical course of heartfailure (HF). It manifests clinically as changes in size, shape, andfunction of the heart.

As a result of damage to the heart, abnormal strain patterns aremanifested in the heart, and the cells that experience a high strainundergo hypertrophy and some loss of function. This affects cardiacfunction and blood pressure parameters, and as a consequence, neuronaland/or hormonal pathways are activated in an attempt to compensate forcardiac damage. For example, poor contraction results in high endsystolic volume (ESV) and thus a reduction in stroke volume (SV). Thismay lead to increase in end diastolic volume (EDV) as well. As cardiacvolumes increase, so does the wall tension in the heart, as known fromLaplace's Law. According to the law, a dilated ventricle requires moretension in the wall to generate the same pressure as would a smallerventricle. This increase in tension increases sympathetic stimulationand vasopressin (antidiuretic hormone or ADH) secretion. Vasopressin isknown to constrict blood vessels and increase heart rate, which causesan increase in blood pressure and an increase in oxygen consumption bythe heart muscle cells. However, this also causes an additional increasein cardiac strain, since the heart beats faster and in every systoleneeds to eject blood against a system showing an increased resistance.This increased strain may cause additional hypertrophy and further lossof function. Thus, a vicious cycle comes into play where thecardiovascular system's attempts at reducing the effect of the damagedtissue cause additional reduction in cardiac performance.

Many attempts have been made to develop devices and methods to treatheart failure, including, for example, devices intended to mechanicallycontrol cardiac volumes:

-   -   U.S. Pat. No. 7,651,461 to Alferness et al., entitled “Cardiac        Support with Metallic Structure,” which is herein incorporated        by reference in its entirety, describes a jacket “configured to        surround the myocardium” which “provides reduced expansion of        the heart wall during diastole by applying constraining surfaces        at least at diametrically opposing aspects of the heart;” and    -   U.S. Pat. No. 7,618,364 to Walsh et al., entitled “Cardiac Wall        Tension Relief Device and Method,” which is herein incorporated        by reference in its entirety, states that “[i]t is believed that        such resistance decreases wall tension on the heart and permits        a diseased heart to beneficially remodel.”

Interfering with cardiac filling may reduce blood pressure inhypertensive patients. One option for interfering with cardiac fillingto reduce blood pressure may be to reduce or even eliminate atrial kick.Atrial kick may provide a relatively small boost to ventricle filling(10-30%) that is caused by atrial contraction before an atrioventricular(AV) valve between the atrium and the ventricle is closed. Once theventricle begins to contract, pressure builds up in the ventricle andcauses the AV valve to passively close. The inventors also found thatwhen effecting treatment that reduces or even eliminates atrial kick,the cardiovascular system acts to adapt to the change and returnperformance values to those that occurred before treatment commenced.International Publications Nos. WO2015/094401 and WO2014/100429, both toMika et al., and both herein incorporated by reference in theirentirety, describe, inter alia, methods and systems providing pacingpatterns of stimulation pulses that comprise pulses configured to reduceor prevent atrial kick and also reduce or even eliminate thecardiovascular system's adaptation to the reduction in blood pressure.The reduction in adaptation may be achieved by reducing neurohormonalresponse to changes in generated pressure and stretch using specificpatterns.

Heart failure patients, on the other hand, typically (although notexclusively) have blood pressure values that are not significantlyelevated. Accordingly, in some cases, it may be preferred to reducecardiac volumes (e.g., at least one of end diastolic volume and endsystolic volume) and/or reduce cardiac strain without significantlyaffecting blood pressure.

The inventors have developed methods and systems of applying cardiacstimulations that yield surprising results in meeting the needs of heartfailure patients. Embodiments provide methods and system that may reducethe strain sensed by cardiac muscles by applying cardiac stimulationsthat reduce at least one of end systolic volume (ESV) and end diastolicvolume (EDV) without significantly affecting the ejection fraction (EF)of the heart, and optionally also without significantly affecting bloodpressure. A reduction of such strain may be useful in reversing cardiacremodeling or at least in slowing down or even stopping the remodelingprocess. In some embodiments, a stimulation pattern may be configured toreduce a neurohormonal response to changes in strain withoutsignificantly affecting blood pressure.

Optionally, when a patient is provided with a cardiac stimulationdevice, a stimulation pattern is selected based on sensing of one ormore of: at least one blood-pressure-related parameter (e.g., anindication of pretreatment and/or treatment blood pressure) and at leastone cardiac-strain and/or volume-related parameter (e.g., a pressuremeasurement within a chamber and/or echocardiogram-derived information).These parameters can be used to adjust one or more of the properties ofone or more (or two or more) pulses in a pulse pattern and/or theproportion between pulses having different settings and/or the order ofthe pulses in the pattern. Optionally, reducing at least one of enddiastolic volume (EDV) and end systolic volume (ESV) suppressessympathetic stimulation, for example, by at least one of reducing wallstrain and hence reducing or eliminating the activation of sympatheticpathways involved with adaptation of the cardiovascular system tochanges.

Optionally, a device is configured to receive feedback informationregarding one or more of the at least one blood-pressure-relatedparameter and at least one cardiac strain/volume related parameter. Thismay be performed periodically (e.g., in a periodic measurement such as aperiodic checkup) and/or ongoing (e.g., with an associated or integralsensor). The information may be received, for example, via communicationwith a user through an input interface and/or by communication withimplanted and/or external devices. Further details of suitable devicesare described below in reference to FIG. 8.

A stimulation setting means one or more parameters of one or morestimulation pulses delivered in a single cardiac cycle. For example,these parameters may include one or more of: a time interval betweenelectrical pulses that are included in a single stimulation pulse (e.g.,AV delay), a period of delivery with respect to the natural rhythm ofthe heart, the length of a stimulation pulse or a portion thereof, andthe site of delivery between two or more chambers. In some embodiments,a pulse setting includes applying an excitatory pulse to a ventricle,timed in synchronization to the natural activity of an atrium of theheart. In some embodiments, a pulse setting includes applying anexcitatory pulse to an atrium timed in synchronization to the naturalactivity of a ventricle of the heart. In some embodiments, a pulsesetting includes applying an excitatory pulse to each of a ventricle andan atrium.

A stimulation pattern may include a series of pulses having identicalstimulation settings or a stimulation pattern may include multiplepulses each having different stimulation settings. For example, astimulation pattern may have one or more pulses having a first settingand one or more pulses having a second setting that is different fromthe first setting. When stating that a stimulation pattern has asetting, it is understood that this means a stimulation pattern mayinclude at least one stimulation pulse having that setting. It is alsounderstood that, in some embodiments a stimulation pattern may includeone or more cardiac cycles where no stimulation pulse is delivered, inwhich case the pulse(s) may be viewed as being delivered at zero power.A stimulation pattern may include a plurality of identical pulses or asequence of pulses including two or more different settings. Twostimulation sequences in a pattern may differ in the order of pulsesprovided within a setting. Two or more stimulation sequences mayoptionally differ in their lengths (in time and/or number ofheartbeats). In some embodiments, a stimulation pattern may includepulses having blood pressure reduction (BPR) settings. In someembodiments, a stimulation pattern may include pulses that do not haveBPR settings.

Experimental Results

In an experiment according to a first embodiment, a plurality ofpatients' hearts were paced at the ventricle and atrium using a pacingpattern that included 9 to 10 pulses having a first stimulation setting(according to which the ventricle was stimulated 40-90 millisecondsafter atrial activation) and 1 to 2 pulses having a second stimulationsetting (according to which the ventricle was stimulated 100-180milliseconds after atrial activation). Pulses having the firststimulation setting reduced atrial kick, while pulses having the secondstimulation setting did not do so. The pacing pattern was appliedcontinuously for a period of up to about six months. Changes in endsystolic volume (ESV), end diastolic volume (EDV), and ejection fraction(EF) were derived from echocardiogram data.

Before treatment, end systolic volume (ESV) and end diastolic volume(EDV) were measured and ejection fraction (EF) was calculated to providebaseline (BL) values for each patient. Thereafter, the same values wereobtained approximately one, two, three, and six months after treatmentcommenced, and the change from baseline (BL) for each patient wascalculated. Each of FIGS. 1-3 depicts results obtained for a pluralityof patients (N), as indicated on the plots. The numbers (N) of patientsincludes only data for which a core lab analysis determined that theechocardiogram was suitable for measurement. The baseline values wereapproximately 110 ml for diastolic volume, approximately 45 ml forsystolic volume, and approximately 62% for ejection fraction.

As shown in FIGS. 1-3, for a period of up to about six months, endsystolic volume (ESV) decreased by approximately 7 ml (about 15%), enddiastolic volume (EDV) decreased by approximately 20 ml (about 17%), andejection fraction (EF) decreased slightly (about a 2% decrease). Thismeans that muscle strain was reduced (due to the lower volume of bloodin the chambers), while the heart's efficiency (as shown by the ejectionfraction (EF)) remained almost unchanged. A reduction of strain worksagainst the vicious cycle of the heart in which cardiac strain plays asignificant role, especially when ejection fraction (EF) is notsignificantly reduced, and thus remodeling is prevented or at least itsprogress rate is reduced. Experimental observations suggest thatbeneficial effects may be obtained over a shorter period, for example,reducing at least one of end systolic volume (ESV) and end diastolicvolume (EDV) by at least 5% and maintaining the at least one of endsystolic volume (ESV) and end diastolic volume (EDV) on average at suchreduced volume for a time period of at least one hour. In particular,according to Laplace's Law, pressure (P) is directly proportional towall tension (T) and inversely proportional to radius (R), such thatP∝T/R. This means that, as long as pressure (P) is maintainedessentially constant, wall tension (T) is a direct function of radius(R). Cardiac volume (V) in turn is a function of R³, so T is a directfunction of V^(1/3). Therefore, when V decreases by approximately 20%, Rdecreases by approximately 7%, and so does T. In other words, a 20%decrease in V is (0.8×V), and (0.8)^(1/3) equals 0.93, yielding(0.93×R), or a 0.07 (or 7%) decrease in R. Extending this analysis tothe at least 5% reduction suggested by the experimental observations,when V decreases by approximately 5%, R decreases by approximately 2%,and so does T.

FIGS. 4-6 illustrate a second set of experimental results according to asecond embodiment, over a longer period of activation time (abouttwenty-four months), and including a greater number of patients. Similarto the first embodiment, in the experiment of the second embodiment, aplurality of patients' hearts were paced at the ventricle and atriumusing a pacing pattern that included 9 to 10 pulses having a firststimulation setting (according to which the ventricle was stimulated40-90 milliseconds after atrial activation) and 1 to 2 pulses having asecond stimulation setting (according to which the ventricle wasstimulated 100-180 milliseconds after atrial activation). Pulses havingthe first stimulation setting reduced atrial kick, while pulses havingthe second stimulation setting did not do so. The pacing pattern wasapplied continuously for a period of up to about twenty-four months.Changes in end systolic volume (ESV), end diastolic volume (EDV), andejection fraction (EF) were derived from echocardiogram data.

Before treatment, end systolic volume (ESV) and end diastolic volume(EDV) were measured and ejection fraction (EF) was calculated to providebaseline (BL) values for each patient. Thereafter, the same values wereobtained eight times after treatment commenced, and the change frombaseline (BL) for each patient was calculated. The eight times were atapproximately the following months after treatment commenced: one, two,three, six, twelve, eighteen, and twenty-four. Each of FIGS. 4-6 depictsresults obtained for a plurality of patients (N), as indicated on theplots. The numbers (N) of patients includes only data for which a corelab analysis determined that the echocardiogram was suitable formeasurement. The baseline values were approximately 115 ml for diastolicvolume and approximately 40 ml for systolic volume.

As shown in FIGS. 4-6, for a period of up to about twenty-four months,end systolic volume (ESV) and end diastolic volume (EDV) remained atreduced levels, with values at the twenty-four month decreased by about9% and 8%, respectively, while ejection fraction (EF) initiallydecreased slightly and insignificantly, and later increased steadily (toabout a 2% increase at twenty-four months). This means that musclestrain was reduced (due to the lower volume of blood in the chambers),while the heart's efficiency (as shown by the ejection fraction (EF))improved slightly. A reduction of strain works against the vicious cycleof the heart in which cardiac strain plays a significant role,especially when ejection fraction (EF) improves, and thus remodeling isprevented or at least its progress rate is reduced. The longer term dataof FIGS. 4-6 therefore demonstrates a slight increase in ejectionfraction (˜60%) with normal global cardiac function over a period oftwenty-four months, which suggests a trend toward continuing improvementof cardiac function beyond that longer term. Thus, in embodiments, astimulation pattern may be configured to reduce the at least one of endsystolic volume (ESV) and end diastolic volume (EDV) by at least 5% andmaintain the at least one of end systolic volume (ESV) and end diastolicvolume (EDV) on average at such reduced volume for a time period of atleast one hour, including as long as three months, twenty-four months,or even longer.

In light of the experimental results, embodiments provide methods andsystems for treating cardiac malfunction. In a first aspect, a methodfor treating cardiac malfunction may include delivering a stimulationpattern of stimulation pulses to at least one cardiac chamber of aheart. At least one of the stimulation pulses may have a firststimulation setting configured to reduce at least one of end systolicvolume (ESV) and end diastolic volume (EDV) in the heart and at leastone of the stimulation pulses may have a second stimulation settingdifferent from the first stimulation setting. The stimulation patternmay be configured to reduce the at least one of end systolic volume(ESV) and end diastolic volume (EDV) by at least 5% and maintain the atleast one of end systolic volume (ESV) and end diastolic volume (EDV) onaverage at such reduced volume for a time period of at least one hour.

FIG. 7 illustrates an embodiment of the first aspect, providing a method700 for treating cardiac malfunction that includes delivering astimulation pattern of stimulation pulses to at least one cardiacchamber of a heart. As shown, in step 702, the method may begin bydelivering at least one stimulation pulse having a first stimulationsetting configured to reduce at least one of end systolic volume (ESV)and end diastolic volume (EDV) in the heart. In step 704, the method maycontinue by delivering at least one stimulation pulse having a secondstimulation setting different from the first stimulation setting.Through the delivery of the stimulation pattern of stimulation pulses ofsteps 702 and 704, the method in step 706 reduces end systolic volume(ESV) and/or end diastolic volume (EDV) by at least 5% and in step 708maintains the reduced end systolic volume (ESV) and/or end diastolicvolume (EDV) on average at such reduced volume for an extended timeperiod (e.g., at least one hour).

In a second aspect, the time period may be at least three months.

In a third aspect, the method of the first or second aspect may includea stimulation pattern configured to reduce cardiac strain by at least 2%and maintain the cardiac strain on average at such reduced strain forthe time period.

In a fourth aspect, the method of any of the preceding aspects mayinclude a stimulation pattern configured to maintain blood pressurewithin an average pressure of ±10% as compared to a pretreatment bloodpressure value for the time period.

In a fifth aspect, the method of any of the preceding aspects mayinclude a stimulation pattern configured to prevent cardiac remodelingin the patient.

In a sixth aspect, the method of any of the preceding aspects mayprovide that the first stimulation setting is configured to reduce orprevent atrial kick in at least one ventricle and at least one of thestimulation pulses has a second stimulation setting different from thefirst stimulation setting.

In a seventh aspect, the method of any of the preceding aspects mayprovide that the first stimulation setting is configured to reduce theat least one of end systolic volume (ESV) and end diastolic volume (EDV)by at least 5% and the second stimulation setting is configured toreduce a baroreflex response or adaptation to the reduction in the atleast one of end systolic volume (ESV) and end diastolic volume (EDV).In some embodiments, the stimulation pattern is configured not toactivate a baroreceptor of the patient.

In an eighth aspect, the method of any of the preceding aspects mayprovide that the stimulation pattern is configured to reduce abaroreflex response or adaptation to the reduction in the at least oneof end systolic volume (ESV) and end diastolic volume (EDV).

In a ninth aspect, the method of any of the preceding aspects mayprovide that the first stimulation setting is configured to reduce theat least one of end systolic volume (ESV) and end diastolic volume (EDV)by at least 5% and the second stimulation setting is configured toreduce a neuronal response or adaptation to the reduction in the atleast one of end systolic volume (ESV) and end diastolic volume (EDV).

In a tenth aspect, the method of any of the preceding aspects mayprovide that the stimulation pattern is configured to reduce a neuronalresponse or adaptation to the reduction in the at least one of endsystolic volume (ESV) and end diastolic volume (EDV).

In an eleventh aspect, the method of any of the preceding aspects mayprovide that the first stimulation setting is configured to reduce theat least one of end systolic volume (ESV) and end diastolic volume (EDV)by at least 5% and the second stimulation setting is configured toincrease hormonal secretion.

In a twelfth aspect, the method of any of the preceding aspects mayprovide that the stimulation pattern is configured to increase hormonalsecretion.

In a thirteenth aspect, the method of any of the preceding aspects mayprovide that the first stimulation setting comprises stimulating aventricle of the heart 40-90 milliseconds after atrial activation.

In a fourteenth aspect, the method of the thirteenth aspect may providethat the second stimulation setting comprises stimulating an atrium ofthe heart to thereby produce atrial stimulation.

In a fifteenth aspect, the method of any of the preceding aspects mayprovide that the second stimulation setting comprises stimulating aventricle of the heart 100-180 milliseconds after atrial activation.

In a sixteenth aspect, the method of any of the first aspect throughfourteenth aspect may provide that the second stimulation settingcomprises allowing a natural AV delay to occur.

In a seventeenth aspect, the method of any of the preceding aspects mayprovide that the stimulation pattern includes at least 4 consecutiveheartbeats having the first stimulation setting for every 1 consecutiveheartbeat having the second stimulation setting.

In an eighteenth aspect, the method of the seventeenth aspect mayprovide that the stimulation pattern includes at least 8 consecutiveheartbeats having the first stimulation setting for every 1 consecutiveheartbeat having the second stimulation setting.

In a nineteenth aspect, the method of any of the preceding aspects mayprovide that the stimulation pattern comprises at least one stimulationpulse having a third stimulation setting different from the first andsecond stimulation settings.

In a twentieth aspect, the method of any of the preceding aspects mayprovide that the cardiac malfunction is associated with an increase inat least one of end systolic volume (ESV) and end diastolic volume(EDV).

In a twenty-first aspect, the method of any of the preceding aspects mayprovide that the cardiac malfunction is congestive heart failure.

In a twenty-second aspect, the method of any of the preceding aspectsmay further include applying the stimulation pattern at a stimulationpattern configuration for a first period, sensing at least one parameterindicative of at least one of end systolic volume (ESV), end diastolicvolume (EDV), cardiac strain, and blood pressure for the first period,and adjusting the stimulation pattern configuration according to thesensing.

In a twenty-third aspect, the method of the twenty-second aspect mayprovide that adjusting the stimulation pattern includes adjusting atleast one of the first stimulation setting and the second stimulationsetting.

In a twenty-fourth aspect, the method of either the twenty-second ortwenty-third aspect may provide that adjusting the stimulation patternconfiguration includes adjusting at least one of the number andproportion of at least one of stimulation pulses having the firststimulation setting and stimulation pulses having the second stimulationsetting within the stimulation pattern.

Another aspect provides a system for treating cardiac malfunction. Thesystem may include a stimulation circuit configured to deliver astimulation pulse to at least one cardiac chamber of a heart of apatient, and at least one controller configured to execute delivery of astimulation pattern of stimulation pulses to the at least one cardiacchamber. At least one of the stimulation pulses may have a firststimulation setting configured to reduce at least one of end systolicvolume (ESV) and end diastolic volume (EDV) in the heart and at leastone of the stimulation pulses may have a second stimulation settingdifferent from the first stimulation setting. The stimulation patternmay be configured to reduce the at least one of end systolic volume(ESV) and end diastolic volume (EDV) by at least 5% and maintain the atleast one of end systolic volume (ESV) and end diastolic volume (EDV) onaverage at such reduced volume for a time period of at least one hour.

In a further aspect of the system, the at least one controller may beconfigured to receive input data relating to at least one sensedparameter indicative of at least one of end systolic volume (ESV), enddiastolic volume (EDV), cardiac strain, and blood pressure for the timeperiod and to adjust the stimulation pattern configuration according tothe at least one sensed parameter.

In a further aspect of the system, the system may further comprise atleast one sensor configured to sense the at least one sensed parameterand to communicate the input data to the at least one controller.

In a further aspect of the system, the at least one controller, thestimulation circuit, and the at least one sensor may be combined in asingle device.

FIG. 8 illustrates an embodiment of a system 800 for treating cardiacmalfunction, which includes a stimulation circuit and at least onecontroller as described above. System 800 may be constructed and havecomponents similar to a cardiac pacemaker essentially as known in theart with some modifications as discussed herein. Optionally, the system,or device, is implantable. Optionally, the system comprises componentsthat may provide additional and/or alternative electrical treatments ofthe heart (e.g., defibrillation). System 800 may be configured forimplantation in the body of a patient essentially as is known in the artfor implantable pacemakers, optionally with some modifications asdiscussed herein.

System 800 may include a biocompatible body 51, one or more controllers52, a power source 53, and a telemetry unit 56. Body 51 may comprise ahousing for encasing a plurality of components of the system.Controller(s) 52 may be configured to control the operation of thesystem, and may implement any of the embodiments and methods disclosedherein. For example, controller(s) 52 may control the delivery ofstimulation pulses. In some embodiments, power source 53 may include abattery. For example, power source 53 may include a rechargeablebattery. In some embodiments, power source 53 may include a battery thatis rechargeable by induction. In some embodiments, telemetry unit 56 maybe configured to communicate with one or more other units and/orcomponents. For example, telemetry unit 56 may be configured tocommunicate with an external programmer and/or a receiving unit forreceiving data recorded on system 800 during operation.

In some embodiments, system 800 may include one or more electrodesand/or sensors. The electrodes and/or sensors may be integrated insystem 800, attached thereto, and/or connectable therewith. In someembodiments, the electrodes may include ventricular electrode(s) 561configured to pace at least one ventricle. Additionally oralternatively, the system may be connected, optionally via wires orwirelessly, to at least one implanted artificial valve 562.Additionally, system 800 may comprise one or more atrial electrode(s) 57for pacing one or more atria, and/or one or more atrial sensors 58 forsensing the onset of atrial excitation, and/or one or more sensors 59for providing other feedback parameters (e.g., a blood-pressure-relatedparameter and a cardiac strain/volume related parameter).

In some embodiments, sensor(s) 59 may comprise one or more pressuresensors, electrical sensors (e.g., ECG monitoring), flow sensors, heartrate sensors, activity sensors, and/or volume sensors. Sensor(s) 59 mayinclude mechanical sensors and/or electronic sensors (e.g., ultrasoundsensors, electrodes, and/or RF transceivers). In some embodiments,sensor(s) 59 may communicate with system 800 via telemetry.

In some embodiments, ventricular electrode(s) 561 and/or atrialelectrode(s) 57 may be standard pacing electrodes. Ventricularelectrode(s) 561 may be positioned relative to the heart at positions asknown in the art for ventricular pacing. For example, ventricularelectrode(s) may be placed in and/or near one or more of the ventricles.In some embodiments, atrial electrode(s) 57 may be placed in and/or nearone or more of the atria. In some embodiments, atrial electrode(s) 57may be attached to the one or more atria at one or more positionsselected to provide early detection of atrial excitation ordepolarization. For example, in some embodiments, atrial electrode(s) 57may be attached to the right atrium near the site of the sinoatrial (SA)node.

One position of ventricular electrode(s) 561 may be such that pacing mayreduce or minimize the prolongation of QRS when the heart is paced, toreduce or even minimize dyssynchrony. In some embodiments, this positionis on the ventricular septum near the Bundle of His. Ventricularelectrode(s) 561 may additionally or alternatively be placed on theepicardium of the heart or in coronary veins. More than one electrodecan be placed on the ventricles to provide biventricular pacing,optionally to reduce dyssynchrony.

System 800 may include a pulse generator, or stimulation circuit,configured to deliver a stimulation pulse to at least one cardiacchamber. The pulse generator, or stimulation circuit, may include someor all standard capabilities of a conventional pacemaker. Controller 52may be configured to control the pulse generator, or stimulationcircuit. Atrial sensor(s) 58 (and optionally other electrode sensorsconfigured to sense other heart chambers) may be connected to system 800via specific circuits that amplify the electrical activity of the heartand allow sampling and detection of the activation of the specificchamber. Other circuits may be configured to deliver stimulation to aspecific electrode to pace the heart, creating propagating electricalactivation.

In some embodiments, one or more additional sensors 59 may be placed inand/or on one or more of the atria and/or in and/or on one or more ofthe ventricles and/or in and/or on one or more other locations thatmight optionally be adjacent the heart. For example, one or more sensorsmay be placed on and/or in vena cava and/or on one or more arteriesand/or within one or more cardiac chambers. These sensors may measurepressure, or other indicators, such as, for example, impedance and/orflow.

In some embodiments, controller 52 may comprise or be a microprocessorpowered by power source 53. In some embodiments, system 800 may comprisea clock 54, for example, generated by a crystal. System 800 may comprisean internal memory 55 and/or be connected to external memory. Forexample, device may connect to an external memory via telemetry unit 56.In some embodiments, telemetry unit 56 may be configured to allowcommunication with external devices such as a programmer and/or one ormore of sensors 59. Any and all feedback information and/or a log ofdevice operation may be stored in internal memory 55 and/or relayed bytelemetry unit 56 to an external memory unit.

In some embodiments, controller 52 may operate in accordance with atleast one embodiment of a method described herein.

In some embodiments, system 800 may comprise one or more sensors forsensing one or more feedback parameters to control the application ofthe AV delay and/or its magnitude.

According to further embodiments, additional systems and devicessuitable for implementing the methods presented herein are described inU.S. Pat. No. 9,370,662 to Mika et al., issued Jun. 21, 2016, forexample, in reference to FIGS. 9 and 14 of that patent. The entirety ofU.S. Pat. No. 9,370,662 is herein incorporated by reference.

The foregoing disclosure has been presented for purposes of illustrationand description. It is not intended to be exhaustive or to limit theembodiments to the precise forms disclosed. Many variations andmodifications of the embodiments described herein will be apparent toone of ordinary skill in the art in light of the above disclosure.

While various embodiments have been described, the description isintended to be exemplary, rather than limiting and it will be apparentto those of ordinary skill in the art that many more embodiments andimplementations are possible that are within the scope of theembodiments. Any feature of any embodiment may be used in combinationwith or substituted for any other feature or element in any otherembodiment unless specifically restricted. Accordingly, the embodimentsare not to be restricted except in light of the attached claims andtheir equivalents. Also, various modifications and changes may be madewithin the scope of the attached claims.

Further, in describing representative embodiments, the specification mayhave presented a method and/or process as a particular sequence ofsteps. However, to the extent that the method or process does not relyon the particular order of steps set forth herein, the method or processshould not be limited to the particular sequence of steps described. Asone of ordinary skill in the art would appreciate, other sequences ofsteps may be possible. Therefore, the particular order of the steps setforth in the specification should not be construed as limitations on theclaims. In addition, the claims directed to the method and/or processshould not be limited to the performance of their steps in the orderwritten, and one skilled in the art can readily appreciate that thesequences may be varied and still remain within the spirit and scope ofthe present embodiments.

What is claimed is:
 1. A system for treating cardiac malfunction,comprising: a stimulation circuit configured to deliver a stimulationpulse to at least one cardiac chamber of a heart of a patient; and atleast one controller configured to execute delivery of a stimulationpattern of stimulation pulses to the at least one cardiac chamber over atime period of at least two months, wherein at least one of thestimulation pulses has a first stimulation setting configured to reduceend systolic volume (ESV) in the heart of the patient and at least oneof the stimulation pulses has a second stimulation setting differentfrom the first stimulation setting, and wherein the stimulation patternis configured to: reduce, during the time period of at least two months,the end systolic volume (ESV) by at least 5%, maintain, during the timeperiod of at least two months, the end systolic volume (ESV) in theheart of the patient on average at such reduced volume, maintain, duringthe time period of at least two months, blood pressure of the patientwithin an average pressure of ±10% as compared to a pretreatment bloodpressure value, and limit, during the time period of at least twomonths, reduction in ejection fraction of the heart to a maximum of 6%reduction and a time average of 2% reduction.
 2. The system of claim 1,wherein the at least one controller is configured to receive input datarelating to at least one sensed parameter indicative of cardiac strainfor the time period of at least two months and to adjust the stimulationpattern according to the at least one sensed parameter.
 3. The system ofclaim 2, further comprising at least one sensor configured to sense theat least one sensed parameter and to communicate the input data to theat least one controller.
 4. The system of claim 3, wherein the at leastone controller, the stimulation circuit, and the at least one sensor arecombined in a single device.
 5. The system of claim 1, the at least onecontroller is configured to receive input data from an artery pressuresensor and to adjust the stimulation pattern according to the inputdata.
 6. A system for treating cardiac malfunction, comprising: astimulation circuit configured to deliver a stimulation pulse to atleast one cardiac chamber of a heart of a patient; and at least onecontroller configured to execute delivery of a stimulation pattern ofstimulation pulses to the at least one cardiac chamber over a timeperiod of at least two months, wherein at least one of the stimulationpulses has a first stimulation setting configured to reduce end systolicvolume (ESV) in the heart of the patient and at least one of thestimulation pulses has a second stimulation setting different from thefirst stimulation setting, and wherein the stimulation pattern isconfigured to: reduce, during the time period of at least two months,the end systolic volume (ESV) by at least 5%, maintain, during the timeperiod of at least two months, the end systolic volume (ESV) in theheart of the patient on average at such reduced volume, maintain, duringthe time period of at least two months, blood pressure of the patientwithin an average pressure of ±10% as compared to a pretreatment bloodpressure value, and reduce cardiac strain, as measured by wall tension,by at least 2% and maintain the cardiac strain on average at suchreduced strain for the time period of at least two months.
 7. A methodfor treating cardiac malfunction, comprising: delivering over a timeperiod of at least two months a stimulation pattern of stimulationpulses to at least one cardiac chamber of a heart of a patient, whereinat least one of the stimulation pulses has a first stimulation settingconfigured to reduce end systolic volume (ESV) in the heart of thepatient and at least one of the stimulation pulses has a secondstimulation setting different from the first stimulation setting;reducing, by delivery of the stimulation pattern over the time period ofat least two months, the end systolic volume (ESV) by at least 5%;maintaining, by delivery of the stimulation pattern over the time periodof at least two months, the end systolic volume (ESV) in the heart ofthe patient on average at such reduced volume for the time period of atleast two months; and maintaining, by delivery of the stimulationpattern over the time period of at least two months, blood pressure ofthe patient within an average pressure of ±10% as compared to apretreatment blood pressure value for the time period of at least twomonths, wherein the stimulation pattern is configured to limit, duringthe time period of at least two months, reduction in ejection fractionof the heart to a maximum of 6% reduction and a time average of 2%reduction.
 8. The method of claim 7, further comprising: receiving inputdata from an artery pressure sensor; and adjusting the stimulationpattern according to the input data.
 9. The method of claim 7, whereinthe stimulation pattern is configured to prevent cardiac remodeling inthe patient.
 10. The method of claim 7, further comprising: applying thestimulation pattern at a stimulation pattern configuration for a firstperiod; sensing cardiac strain for the first period; and adjusting thestimulation pattern configuration according to the sensing.
 11. Themethod of claim 7, wherein the first stimulation setting is configuredto reduce the end systolic volume (ESV) by at least 5% and the secondstimulation setting is configured to reduce a baroreflex response oradaptation to the reduction in the end systolic volume (ESV).
 12. Themethod of claim 7, wherein the stimulation pattern is configured toreduce a baroreflex response or adaptation to the reduction in the endsystolic volume (ESV).
 13. The method of claim 7, wherein thestimulation pattern is configured to reduce a neuronal response oradaptation to the reduction in the end systolic volume (ESV).
 14. Themethod of claim 7, wherein the stimulation pattern is configured toincrease hormonal secretion.
 15. The method of claim 7, wherein thestimulation pattern comprises at least one stimulation pulse having athird stimulation setting different from the first and secondstimulation settings.
 16. The method of claim 7, wherein the cardiacmalfunction is congestive heart failure.
 17. The method of claim 7,further comprising: applying the stimulation pattern at a stimulationpattern configuration for a first period; sensing at least one parameterindicative of at least one of end systolic volume (ESV), end diastolicvolume (EDV), cardiac strain, or blood pressure for the first period;and adjusting the stimulation pattern configuration according to thesensing.
 18. The method of claim 17, wherein the adjusting thestimulation pattern configuration includes adjusting at least one of thefirst stimulation setting or the second stimulation setting.
 19. Themethod of claim 17, wherein the adjusting the stimulation patternconfiguration includes adjusting at least one of a number or proportionof at least one of stimulation pulses having the first stimulationsetting or stimulation pulses having the second stimulation settingwithin the stimulation pattern.
 20. The method of claim 7, furthercomprising: delivering the stimulation pattern for twenty-four months;reducing, by delivery of the stimulation pattern from twelve months totwenty-four months, the end systolic volume (ESV) on average by at least5% from twelve months to twenty-four months; and maintaining, bydelivery of the stimulation pattern from twelve months to twenty-fourmonths, blood pressure of the patient within an average pressure of ±10%as compared to a pretreatment blood pressure value from twelve months totwenty-four months.
 21. A method for treating cardiac malfunction,comprising: delivering over a time period of at least two months astimulation pattern of stimulation pulses to at least one cardiacchamber of a heart of a patient, wherein at least one of the stimulationpulses has a first stimulation setting configured to reduce end systolicvolume (ESV) in the heart of the patient and at least one of thestimulation pulses has a second stimulation setting different from thefirst stimulation setting; reducing, by delivery of the stimulationpattern over the time period of at least two months, the end systolicvolume (ESV) by at least 5%; maintaining, by delivery of the stimulationpattern over the time period of at least two months, the end systolicvolume (ESV) in the heart of the patient on average at such reducedvolume for the time period of at least two months; and maintaining, bydelivery of the stimulation pattern over the time period of at least twomonths, blood pressure of the patient within an average pressure of ±10%as compared to a pretreatment blood pressure value for the time periodof at least two months, wherein the stimulation pattern is configured toreduce cardiac strain, as measured by wall tension, by at least 2% andmaintain the cardiac strain on average at such reduced strain for thetime period of at least two months.
 22. A method for treating cardiacmalfunction, comprising: delivering over a time period of at least threemonths a stimulation pattern of stimulation pulses to at least onecardiac chamber of a heart of a patient, wherein at least one of thestimulation pulses has a first stimulation setting configured to reduceend systolic volume (ESV) in the heart of the patient and at least oneof the stimulation pulses has a second stimulation setting differentfrom the first stimulation setting; reducing, by delivery of thestimulation pattern over the time period of at least three months, theend systolic volume (ESV) by at least 5%; maintaining, by delivery ofthe stimulation pattern over the time period of at least three months,the end systolic volume (ESV) in the heart of the patient on average atsuch reduced volume for the time period of at least three months; andmaintaining, by delivery of the stimulation pattern over the time periodof at least three months, blood pressure of the patient within anaverage pressure of ±10% as compared to a pretreatment blood pressurevalue for the time period of at least three months, wherein the firststimulation setting comprises stimulating a ventricle of the heart 40-90milliseconds after atrial activation, wherein the second stimulationsetting comprises stimulating the ventricle of the heart 100-180milliseconds after atrial activation, and wherein the stimulationpattern includes at least 4 consecutive heartbeats having the firststimulation setting for every 1 consecutive heartbeat having the secondstimulation setting.